Hydroxydibenzo(a,d)cyclohepten-5-ones and esters and ethers thereof



United States Patent 3,507,920 HYDROXYDIBENZO[a,d]CYCLOHEPTEN-S-ONES AND ESTERS AND ETHERS THEREOF John W. Schulenberg and Sydney Archer, Bethlehem, N.Y., assignors to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application Oct. 16, 1964, Ser. No. 404,506, now Patent No. 3,350,405, dated Oct. 31, 1967. Divided and this application Apr. 24, 1967, Ser.

Int. Cl. C07c 85/06, 87/06 US. Cl. 260-59 1 Claim ABSTRACT OF THE DISCLOSURE Di'benzo[a,d]cyclohepten ones and 10,11-dihydro derivatives thereof substituted on one of the benzene rings by an amino-lower-alkoxy group are prepared by reacting the corresponding hydroxydibenzo[a,b]cycloheptene-S-ones with an amino-lower-alkyl halide. The S-carbonyl group is subsequently converted by reduction, Grignard and dehydration reactions to the groups CH CH( OH C(lo-wer-alkyl) (OH), C(phenyl-lower-alkyl) (OH), C: lower-alkylidene), C: (phenyl-loWer-alkylidene), CH(lower-alkyl) or CH(phenyl-lower-alkyl). The compounds are useful as antidepressant agents.

This application is a division of copending application Ser. No. 404,506, filed Oct. 16, 1964, now US. Patent 3,350,405.

This invention relates to tricyclic compounds, and in particular is concerned with dibenzo[a,b]cyclohepten-5- ones substituted on one of the benzene rings by an amino-lower-alkoxy group, and derivatives thereof.

The compounds of the invention have the following general formula:

3,507,920 Patented Apr. 21, 1970 araliphatic type that imparts to the molecules which contain it sufiicient basicity (ionization to the extent of at least 10 so that the compounds readily form acidaddition salts with strong inorganic and organic acids. A particularly preferred group of amino radicals include amino (NH lower-alkylamino, cycloalkylamino, (phenyl-lower-alkyl)amino, di-lower-alkylamino, dicycloalkylamino, N (cycloalkyl) lower alkylamino, po1ymethylenimino of 5-7 ring members, 4-morpholinyl, lpiperazinyl, 4-lower-alkyl-l-piperazinyl, 4-phenyl-1-piperazinyl, di-(phenyl-lower-alkyl)amino, and N-(phenyllower-alkyl)-lower-a1kylamino. In the foregoing groups, lower-alkyl has from one to six carbon atoms, and cycloalkyl has from five to six ring members, including cyclopentyl, cyclohexyl and lower-alkyl-substituted cyclopentyl and cyclohexyl. Polymethylenimino of 5-7 ring members includes l-pyrrolidyl, l-piperidyl, l-hexamethyleniminyl and lower-alkylated derivatives thereof.

In the above Formula I, X stands for ethylene (CH CH or vinylene (CH CH).

In the above Formula I, Y stands for a lower-alkylene bridge having its connecting valences on different carbon atoms and contains at least two and not more than about five carbon atoms, thus including such radicals as CH CH CH CH CH -CH(CH )CH -CH (CH )CH(CH -CH CH CH CH -CH CH CH CH CH and the like.

In the above Formula I, Z stands for the carbonyl group or divalent groups derived therefrom. The latter include methylene (CH carbinol [CH(OH)], loweralkylcarbinol [C(lower-alkyl)(OH)], phenyl-loWer-alkylcarbinol [C(phenyl-lower-alkyl) (OH)], C: (loweralkylidene), C: (phenyl-lower-alkylidene), CH(loweralkyl) and CH(phenyl-l0'wer-alkyl). The lowenalkyl and lower-alkylidene groups contain from one to about six carbon atoms.

The the above Formula I, the side-chain OYN=B can be in any position of the benzene ring, preferably in the 1-, 2- or 3-p-ositions. The benezene rings of the tricyclic system as well as any phenyl groups present in the groups -N=B and Z can bear additional substituents inert under the conditions employed in preparing the compounds. Such additional substituents include lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkylsulfinyl and lower-alkylsulfonyl of one to six carbon atoms; halogen (including fluorine, chlorine, bromine and iodine); trifluoromethyl, and the like.

The compounds of Formula I wherein X is CH CH and Z is C=O are prepared as follows:

omooon f 0 t C I NaOAc 2H2(Ni) I O 0 OR l l CHzCHz CHzCHz l ACCKHZSO-t) AlCl OR or pol hos- \COOH phoi ig acid O Phthalic anhydride is condensed with a lower-alkoxythe desired aminoalkoxy-SH-dibenzo[a,d]cyclohepten-S- phenylacetic acid (R is lower-alkyl of 1-6 carbon atoms) in the presence of anhydrous sodium acetate to give a lower-alkoxybenzylidenephthalide (III). The latter hydrogenated in the presence of Raney nickel is converted to a 2-[2-(lower-alkoxyphenyl)ethyl]benzoic acid (IV), which is then cyclized in the presence of polyphosphoric acid or acetyl chloride and sulfuric acid to give a loweralkoxy 10,11 dihydro-5H-dibenzo[a,d]cyclohepten-S- one (V). The latter is dealkylated with anhydrous aluminum chloride to hydroxy-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-one (VI), which is then reacted with an aminoalkyl halide (Hal-YN=B) in the presence of a strong base, such as an alkali metal alkoxide, hydride, or amide, to produce an amino-lower-alkoxy-10,l1-dihydro 5H dibenzo[a,d]cy1ohepten 5 one (I; X is CH 'CH Z is CO). The halogen (Hal) of the aminoalkyl halide, HalYN=B, can be any of the halogens, chlorine, bromine and iodine.

The compounds of Formula I wherein X is CH=CH and Z is 0 0 are prepared as follows:

VII

1) NBS 2) pyridine VIII CH=GH CH=OH I (X iS CH=CH, Z i8 00) one (I; X is CH=CH, Z is Co).

The compounds of Formula I wherein Z stands for a divalent group other than carbonyl and derived therefrom are prepared as follows:

Z is CH by catalytic hydrogenation (palladium-oncharcoal) or by Wolff-Kishner reduction (alkaline treatment of the hydrazone) of compounds where Z is CO.

Z is CH(OH): by lithium aluminum hydride reduction of compounds where Z is CO.

Z is C(lower-alkyl)OH or C(phenyl-lower-alkyl)OH: by reacting a compound where Z is CO with a loweralkyl or phenyl-lower-alkyl Grignard reagent.

Z is (lower-alkylidene) or C=(phenyl-lower-alkylidene): by dehydration, by means of acidic reagents, of compounds where Z is C(lower-alkyl)OH or C(phenyllower-alkyl)OH, respectively.

Z is CH(lower-alkyl) or CH(phenyl-lower-alkyl): by catalytic hydrogenation (palladium-on-charcoal) of compounds where Z is C:(lower-alkylidene) or C=(phenyllower-alkylidene), respectively.

The transformations of the carbonyl group can, of course, be carried out on intermediates, e.g., those of Formulas VI and IX, prior to introducing the aminolower-alkyl side-chain.

When the radical N=B in the above Formula I stands for an amino group other than tertiary-amino, that is, when there is at least one hydrogen atom attached to the nitrogen, it is preferred to use alternative routes of synthesis. One of these routes comprises condensing a compound of Formula VI or IX with an N-benzyl-N- (R)-amino-lower-alkyl halide, wherein R is lower-alkyl or cycloalkyl, in the presence of a strong base in the manner already described, and then subjecting the resulting N-benzy-N-(R')-amino-lower-alkoxy compound to hydrogenolysis to remove the benzyl group and thus produce a compound of Formula I wherein N=B is NHR. Alternative, the N-benzyl group can be displaced by a carbethoxy group by reacting it with ethyl chloroformate and the resulting urethane cleaved by alkaline hydrolysis.

Still another way of introducing the amino-lower-alkoxy side-chain comprises reacting a compound of Formula VI or IX with a lower-alkylene oxide, thereby forming a compound with a hydroxy-lower-alkoxy side-chain, O--Y-OH, converting the latter to the p-toluenesulfonate ester, and then reacting the latter with ammonia or the appropriate amine, HN=B.

When a compound of the invention is treated with an equivalent amount of an inorganic or organic acid, it is converted to an acid-addition salt form. The salt form is the full equivalent of the free base insofar as the inherent properties of the cationic moiety is concerned. Watersoluble salt forms derived from acids Whose anions are pharmaceutically acceptable are of special interest for therapeutic use, but salt forms which are water-insoluble or contain toxic anions are useful as characterizing derivatives of the free bases, or as intermediates in the purification of the free bases or in the preparation of other salts by ion exchange reactions.

Pharmacological testing of compounds of Formula I has demonstrated that they are useful as antidepressant agents as evidenced by their ability to prevent and reverse reserpine ptosis in mice and by the fact that they inhibit the enzyme phenylamine B-hydroxylase in vitro. Anticonvulsant and psychomotor activity have also been found in the compounds of the invention.

The structures of the compounds of the invention were established by elementary analyses, by the modes of preparation and by ultraviolet and infrared spectra.

The following examples will further illustrate the invention without the latter being limited thereby.

EXAMPLE 1 (a) m-Anisylidenephthalide [111; OR is m-OCH ].A mixture of 99.5 g. of m-methoxyphenylacetic acid, 78.9 g. of phthalic anhydride and 6 g. of anhydrous sodium acetate was heated gradually to 260 C. in a Woods metal bath over a period of forty minutes and held at this temperature for about seventy-five minutes while allowing the mixture to distill. The reaction mixture was cooled, 1000 ml. of ethanol was added, and the solid product was collected by filtration and washed with hot ethanol. The product was recrystallized from ethanol to give 97.9 g. of m-anisylidenephthalide in the form of yellow-tan needles, M.P. 120.5-122 C. (uncorr.).

(b) 2- [2-(m-methoxyphenyl)ethyl]benzoic acid [IV; OR is mOCH ].A mixture of 212.9 g. of m-anisylidenephthalide and 1600 ml. of absolute ethanol was hydrogenated in the presence of 200 g. of Raney nickel catalyst until two molar equivalents of hydrogen had been absorbed. The hydrogenation was complete in about three hours, and the catalyst was removed by filtration. The filtrate was evaporated to dryness and the residue was taken up in 1 liter of chloroform and stirred and heated with 60 g. of sodium bicarbonate in 3 liters of water. The aqueous solution was separated, filtered and acidified, and the precipitated acid was collected, washed with water and dried for twenty-four hours at 60-70 C. over phosphorous pentoxide to give 83.3 g. of 2- [Z-(m-methoxyphenyl) ethyl]benzoic acid, M.P. 116.8-119 C. (uncorr.).

(c) 2 methoxy 10,11-dihydro-5H-dibenzo [a,d]cyclohepten-S-one [V; OR is 2OCH ].-2-[2-m-methoxyphenyl)ethyl]benzoic acid (10.25 g.) and 100 ml. of acetyl chloride were stirred and warmed until solution was complete. Sulfuric acid (0.5 ml.) was added, followed by stirring while allowing the excess acetyl chloride to boil off over a period of forty minutes. The resulting orange solution was poured into 400 ml. of water and the solid product was collected by filtration. The product was recrystallized from aqueous ethanol and dried over phos phorous pentoxide for sixty hours to give 7.4 g. of 2- methoxy 10,11 dihydro-SH-dibenzol[a,d]cyclopenten-5- one in the form of colorless needles, M.P. 7l.2-73.5 C. (uncorr.); ultraviolet maxima at 238 and 300 m (6: 9,300 and 14,300), infrared absorption at 6.18, 6.29 and 6.37[.L.

(d) 2 hydroxy 10,11-dihydro-5H-dibenzo [a,d]cyclohepten-S-one [VI; 2OH].A mixture of 11.94 g. of 2- methoxy 10,11 dihydro-5H-dibenzo[a,d] cyclohephen-S- one, 20.0 g. of anhydrous aluminum chloride and 250 ml. of toluene was stirred under reflux for one and three-quarter hours. The excess aluminum chloride was decomposed by addition of ice water, and the solid products was collected by filtration and washed with Water. The benzene layer was concentrated to dryness and the residue combined with the filtered solid product. The com-bined product was suspended in methanol and the suspension filtered and concentrated to dryness. The latter residue was suspended in 5% sodium hydroxide solution, filtered, and the filtrate made acid with acetic acid. The precipitated product was collected, suspended in methanol and the insoluble material removed by filtration. The filtrate was concentrated to a volume of less than 500 ml. and Water was added to the point of turbidity. The solution was chilled and the product collected to give 11.06 g. of 2-hydroxy-10,1l-dihydro-SH-di'benzo [a,d] cyclohepten-S-one in the form the yellow plates, M.P. 141.4-143.8 C. (corn) when recrystallized from aqueous methanol.

2 acetoxy-10,1l-dihydro-SH-dibenzo[a,dJcyclohepten- S-one was prepared by treating 2-hydroxy-l0,11-dihydro- SH-dibenzo[a,dJcyclohepten-S-one with an excess of acetic anhydride in pyridine solution, and was obtained in the form of colorless plates, M.P. 64-65 C. (uncorr.).

EXAMPLE 2 (a) p-Anisylidenephthalide [III; OR is pOCH was prepared from 166.2 g. of p-methoxyphenylacetic acid, 141.1 g. of phthalic anhydride and 10.0 g. of anhydrous sodium acetate according to the procedure described above in Example 1, part (a), and was obtained in the form of yellow needles (129 g.), M.P. 145.8-148.0 C. (uncorr.).

(b) 2-[2-(p-methoxyphenyl)ethyl]benzoic acid [IV; OR is pOCH was prepared by hydrogenation of 126.1 g. of p-anisylidenephthalide according to the procedure described above in Example 1, part ('b). There was thus obtained 84.5 g. of 2-[Z-(p-methoxyphenyl)ethyl]benzoic acid, M.P. 117.5-118.5 C. (uncorr.).

(c) 3 methoxy 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-one [V; OR is 3OCH ].A mixture of 10.25 g. of 2-[2-(p-methoxyphenyl)ethyl]benzoic acid and 75 ml. of polyphosphoric acid was stirred and heated at C. for five hours. The reaction mixture was added to 800 ml. of water, extracted with choloform, and the chloroform extracts washed with water, saturated sodium chloride solution, and filtered. Excess dilute sodium carbonate solution (300 ml.) was added, and the mixture stirred and warmed to evaporate the chloroform. The resulting suspension was extracted with ether and with choloroform, and the organic extracts were washed with water, saturated sodium chloride, dried and concentrated to give 8.63 g. of 3-methoxy-10, l l-dihydro-SH-dibenzo [a,d] cyclohepten- 5-one which was used in the following procedure without further purification.

(d) 3 hydroxy 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-one [VI; 3-OH] was prepared from 2.88g. of 3 methoxy 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten- 5-one and 5.0 g. of aluminum chloride according to the procedure described above in Example 1, part ((1). The product was recrystallized from methanol to obtain 3-hydroxy 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one in the form of light tan platelets, M.P. 146l47.2 C. (uncorr.).

By replacing the m-methoxyphenylacetic acid in Example 1 by a molar equivalent amount of o-methoxyphenylacetic acid and carrying it through the succeeding transformations, there can be obtained 1-hydroxy-10,l1-dihydro-SH-dibenzo[a,d]cyclohepten-5-one [VI; 1OH] By replacing the phthalic anhydride in Example 1 by a molar equivalent amount of 3,4-dimethoxyphthalic anhydride or 3,4-dimethylphthalic anhydride there can be obtained, respectively, 2-hydroxy-7,8-dimethoxy-10,ll-dihydro-SH-dibenzo[a,d]cyclohepten-5-one or 2-hydroxy- 7,8 dimethyl 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one.

EXAMPLE 3 (a) 2 acetoxy 5H dibenzo[a,dJcyclohepten-S-one [VIII;OAcyl is 2OCOCH ].A mixture of 2.66 g. of [VIII; OAcyl is 2OCOCH ].A mixture of 2.66 g. of 5-one [Example 1, part (d)], 2.14 g. of N-bromosuccinimide, 0.11' g. of benzoyl peroxide and 50 ml. of carbon tetrachloride was stirred at reflux for one and onehalf hours. The reaction mixture was filtered into 50 ml. of pyridine and allowed to stand at room temperature for three days. The mixture was then heated while distilling off the carbon tetrachloride and pyridine over a period of five hours. The residue was added to water, the product was collected, Washed with water, dried and recrystallized from petroleum ether (Skellysolve C) to give 1.57 g. of 2-acetoxy-5H-dibenzo[a,dJcyclohepten-S-one in the form of pale yellow plates, M.P. l02.5105.5 C. (uncorr.).

(b) 2 hydroxy 5H dibenzo[a,d]cyclohepten-5-one [IX; 2OH].-A mixture of 1.53 g. of 2-acetoxy-5Hdibenzo[a,d]cyclohepten-5-one and 50 ml. of 5% aqueous sodium hydroxide was allowed to stand at room temperature'overnight, and then was stirred for one hour and filtered. The filtrate was saturated with carbon dioxide and the precipitated product was collected and recrystallized from aqueous methanol to give 1.18 g. of 2-hydroxy- H-dibenzo[a,d]cyclohepten-S-one as a light tan solid, M.P. 195198 C. (uncorr.); ultraviolet maxima at 226, 249, 279 and 350 m (e:13,500, 22,900, 36,100 and 3,350), infrared absorption at 6.25, 6.40, 6.49 and 7.02;.

By replacing the 2-acetoxy-l0,1l-dihydro-SH-dibenzo- [a,d]cyclohepten-5-one in Example 3, part (a) by a molar equivalent amount of the acetates of 3-hydroxy-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S- one,

1-hydroxy-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5- one,

2-hydroxy-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d]

cyclohepten-S-one or 2-hydroxy-7,8-dimethyl-10,1l-dihydro-SH-dibenzo[a,d]

cyclohepten-S-one there can be obtained, respectively,

3-hydroxy-5H-dibenzo [a,d] cyclohepten-S -one, 1-hydroxy-5 H-dibenzo [a,d] cyclohepten-S -one, 2-hydroxy-7,8-dimethoxy-5H-dibenzo [a,d] cyclohepten-S- one or 2-hydroxy-7,S-dimethyl-SH-dibenzo a,d] cyclohepten-S- one.

EXAMPLE 4 2 hydroxy 10,1l-dihydro-SH-dibenzo[a,d]cycloheptene.A solution of 5.84 g. of 2-hydroxy-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-S-one [Example 1, part (d)] in 200 ml. of acetic acid was hydrogenated in the presence of 1.74 g. of palladium-on-charcoal catalyst. The hydrogenation was complete in sixteen hours, the catalyst was removed by filtration and the filtrate concentrated to dryness. The residue was dissolved in dilute aqueous sodium hydroxide, the solution filtered and saturated with carbon dioxide. The product was collected, dried and recrystallized from benzene to give 4.54 g. of 2-hydroxy- 10,1l-dihydro-SH-dibenzo[a,d]cycloheptene in the form of light tan platelets, M.P. 164.5-l67 C. (uncorr.).

By replacing the 2-hydroxy-10,ll-dihydro-SH-dibenzo- [a,d]cyclohepten-5-one in the foregoing preparation by a molar equivalent amount of S-hydroxyl 0,1 l-dihydro-SH-dibenzo [a,d] cyclohepten-S- one, 1-hydroxy-10,1 l-dihydro-SH-dibenzo [a,d] cyclohepten-S- one,

8 2-hydroxy-7,8-dimethoxy-10,1 I-dihydro-SH-dibenzo [a,d]

cyclohepten-S-one or 2-hydroxy-7,8-dimethyl-10,1l-dihydro-SH-dibenzo[a,d]

cyclohepten-S-one there can be obtained, respectively,

3-hydroxy-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene, 1-hydroXy-l0,1 1-dihydro-5H-dibenzo[a,d]cycloheptene, 2-hydroXy-7,8-dimethoxy-10,1l-dihydro-SH-dibenzo[a,d]

cycloheptene, or 2-hydroxy-7,8-dimethyl-10,11-dihydro-5H-dibenzo[a,d]

cycloheptene.

EXAMPLE 5 2 (2 diethylaminoethoxy) 10,11 dihydro-SH-dibenzo[a,d]cyclohepten-5-one [I; X is CH CH Y is CH CH Z is CO, N B is N(C H ].-2-hydroxy-10, 1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one (8.38 g.) (Example 1) and 2.52 g. of sodium methoxide were suspended in 300 ml. of chlorobenzene. The mixture was distilled until the head temperature reached 132 C. The suspension was cooled and 6.34 g. of Z-diethylaminoethyl chloride was added. The reaction mixture was stirred under reflux for two and one-half hours. There was then added 40 ml. of 35% aqueous sodium hydroxide, the layers were separated and the sodium hydroxide solution washed with chloroform. The combined organic extracts were washed three times with water and twice With saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvents were evaporated, the residue dissolved in 200-250 ml. of ether and an excess of ethereal hydrogen chloride was added. The hydrochloride salt which separated was collected and recrystallized from an isopropyl alcohol-ether mixture to give 9.10 g. of 2 (2-diethy1aminoethoxy)-10,1l-dihydro-SH-dibenzo- [a,d]cyclohepten-5-one in the form of its hydrochloride salt, pale yellow needles, M.P. 118.6120.4 C. (com).

2 (Z-diethylaminoethoxy)-10,ll-dihydro-SH-dibenzo- [a,dJcyclohepten-S-one was found to be active in reversing ptosis at mg./kg. when injected intraperitoneally to mice medicated with 2 mg./kg. of reserpine; and was found to be 204% as active as imipramine in inhibition of phenylamine fl-hydroxylase in vitro.

The examples in the following table were prepared according to the procedure described in Example 5, using the appropriate starting material of Examples 1-4 and the appropriate aminoalkyl halide. The compounds of the table have antidepressant activities similar to those of the compound of Example 5.

Position M.P., C.

of Side (corn) of Z YN:B Chain HCl salt C=O CH2CH2N(C2H5)2 2 140. 8-142. 2

0:0 CH2CH2CH2N(CH:)2 2 193. 12-193. 8

0:0 CH2CH2N( CH3 2 183. 8-186. 0

C=O CH2CH2CH2N(CH3)2 2 193. 6-194. 8

C=O CH2CH2N(CH3)2 2 211. 2-212. 8

(3:0 CHQCH2N(CH3)(CH2C6H5) 2 165. 8-175. 0

(3:0 CH2CH2N(CHB) (OHzCtHt) 2 199. 2-200. 8

/CHzCHz (3 0 CHzCHzN 2 182. 8-184. 2

CHzGH /OH2CH2 14 CH OH 0:0 CHzCI-IzN 2 201. 0-202. 6

CHzCHz CHZCHZ 15 CH=OH 0 0 CH2CH2N /CH2 2 199. 2200.6

CHzCHz CHzCHz 16 CHzCHz 0:0 CHzCHzN /CH2 2 171. 2-173.8

CHzCHz 17 OHzCHz 0:0 CH2CH2N CII3 2 3 168. 6-170.6

18. CHZCHQ CH2 CH2CH2N(CHz)z 2 173. 0175.0

By replacing the Z-diethylaminoethyl chloride in Example by a molar equivalent amount of Z-dimethylaminopropyl chloride, S-dimethylaminopentyl chloride, 2- dicyclohexylaminoethyl chloride, 2-(N-cyclopentyl) (N- methyl)aminoethyl chloride, 2-(1-hexamethyleniminyl) ethyl chloride, 2-(4-morpholinyl)ethyl chloride, 2-(1-piperazinyl)ethyl chloride, 2-(4-methyl-1-piperazinyl)ethyl chloride, 2 (4 a phenyl 1 piperazinyl)ethyl chloride, 2 dibenzylaminoethyl chloride or 2 (4-methyl l-piperidyl)ethyl chloride there can be obtained, respectively, 2-(2-dimethylaminopropoxy)-10,1l-dihydro 5H- dibenzo [a,d] cyclohepten-S-one, 2- S-dimethylarninopentoxy) 10,11-dihydro 5H-dibenzo[a,d]cyclohepten 5- one, 2-(2-dicyclohexylaminoethoxy) 10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5-one, 2-[2-(N-cyclopentyl) (N- methyl)aminoethoxy] 10,11-dihydro 5H-dibenzo[a,d] cyclohepten-S-one, 2- [2- l-hexamcthylenirninyl) ethoxy] 10,11-dihydro SH-dibenzo[a,d]cyclohepten-5-one, 2-[2- (4-morph0linyl)ethoxy]lO,l l-dihydro SH-dibenzo [a,d] cyclohepten S-one, 2-[2-(1-piperazinyl)ethoxy]-10,1l-dihydro SH-dibenzo[a,d]cyclohepten 5 one, 2-[2-(4- methyl l-piperazinyl)ethoxy] 10,11-dihydro SH-dibenzo[a,d]cyclohepten 5-one, 2-[2-(4-phenyl l-piperazinyl)ethoxy] 10,11-dihydro 5H-dibenzo[a,d]cyclohepten 5-one, 2-(Z-dibenzylaminoethoxy)-10,1l-dihydro- SH-dibenzo[a,d]cyclohepten-5-one, or 2-[2-(4-methyl 1- piperidyl)ethoxy]10,11-dihydro 5H-dibenzo[a,d]cyclohepten-S-one.

By replacing the 2-hydroxy-10,1l-dihydro-SH-dibenzo [a,d]cyclohepten-5-one in Example 5 by a molar equivalent amount of 2-hydroxy-7,8-dimeth0xy-10,1l-dihydro- SH-dibenzo[a,d]cyclohepten S-one, Z-hydroxy 7,8-dimethyl 10,11-dihydro SH-dibenzo[a,d]cyclohepten-5- one, 3-hydroxy SH-dibenzo [a,d]cyclohepten 5-one, 1- hydroxy SH-dibenzo[a,d]cyclohepten-5-one, 2-hydroxy- 7,8-dimethoxy SH-dibenzo[a,d]cyclohepten-5-one, 2-hydroxy-7,8-dimethyl SH-dibenzo a,d] cyclohepten-S-one, 3-hydroxy 10,11-dihydro 5H-dibenzo[a,d] cycloheptene, l-hydroxy 10,11-dihydro 5H-clibenzo[a,d] cycloheptene, 2-hydroxy 7,8-dimethoxy 10,11-dihydro SH-dibenzo [a,d]cycloheptene or 2-hydroxy 7,8-dimethyl-10,11-dihydro 5H-dibenzo[a,d]cycloheptene there can be obtained, respectively, 2-(2-diethylaminoethoxy) 7,8-dimethoxy 10,11-dihydro 5H-dibenzo[a,d]cyclohepten- 5-one, 2-(2-diethylaminoethoxy)-7,8-dimethyl 10,11-dihydro SH-dibenzo[a,d]cyclohepten-5-one, 3-(2-diethy1- aminoethoxy) 5H-dibenzo[a,d]cyclohepten-5-one, 1-(2- diethylaminoethoxy) SH-dibenzo[a,d]cyclohepten 5- one, 2-(2-diethylaminoethoxy) 7,8-dimethoxy SH-dibenzo[a,d] cyclohepten 5-one, 2-(2-diethy1aminoethoxy)- 7,8-dimethyl 5H-dibenzo[a,d]cyclohepten S-one, 3-(2- diethylaminoethoxy) 10,11-dihydro 5H-dibenzo[a,d] cycloheptene, 1-(2-diethylaminoethoxy) 10,11-dihydro- SH-dibenzo [a,d] cycloheptene, 2- 2-diethylaminoethoxy 7,8-dimethoxy 10,11-dihydro 5H-dibenzo[a,d]cycloheptene or 2-(2-diethylaminoethoxy 7,8-dimethyl-10,11- dihydro-SH-dibenzo [a,d] cycloheptene.

EXAMPLE 19 S-benzyl 2-(2-diethylaminoethoxy)-10,1l-dihydro 5- hydroxy SH-dibenzo[a,d]cycloheptene [I; X is CH CH Y is CH CH Z is C(OH) (CH C H N=B is N(C H ].-2-(2-dietl1ylaminoethoxy) 10,11-dihydro- SH-dibenzo[a,d]cyclohepten 5-one in the form of its hydrochloride salt (5.00 g.) (Example 5) was converted to the free base with a slight excess of aqueous sodium carbonate solution. The base was extracted with ether, the ether extract washed with Water and saturated sodium chloride solution, dried over anhydrous calcium sulfate and concentrated to a volume of 50 ml.

A few drops of benzyl chloride was added to 0.71 g. of magnesium turnings covered by 40 ml. of dry ether, reaction was initiated with a stirring rod, and the remainder of 3.52 g. of benzyl chloride was added over a period of ten minutes. The Grignard reagent was stirred at reflux for fifteen minutes and then the ether solution containing 2 (2 diethylaminoethoxy) 10,11 dihydro 5H dibenzo[a,d]cyclohepten-S-one was added over a period of ten minutes. The reaction mixture was refluxed for three and one-half hours, ice was added and the mixture was filtered. The aqueous layer was extracted with ether and the combined ether layers were dried over anhydrous magnesium sulfate and concentrated. The residue was triturated with hexane to give 4.24 g. of 5-benzyl-2-(2-diethylaminoethoxy) 10,11 dihydro 5 hydroxy 5H dibenzo[a,d]cycloheptene, M.P. 70.281.0 C. (corr.).

EXAMPLE 20 5 (p chlorobenzyl) 2 (2 diethylaminoethoxy)- 10,11 dihydro 5 hydroxy 5H dibenzo[a,d]cycloheptene [I; X is CH CH Y is CH CH Z is N=Bis N(C H was prepared from 2-(2-diethylaminoethoxy) 10,11 dihydro 5H dibenzo[a,d]cyclohepten-S-one (from 15.68 g. of the hydrochloride salt) and the Grignard reagent from 2.22 g. of magnesium and 14.05 g. of p-chlorobenzyl chloride according to the procedure described above in Example 19. The crude product was recrystallized from hexane to give 6.77 g. of S-(pchlorobenzyl) 2 (2 diethylaminoethoxy) 10,11 dihydro 5 hydroxy 5H dibenzo[a,d]cycloheptene, M.P. 90.095.0 C. (corn).

5 (p chlorobenzyl) 2 (2 diethylaminoethoxy)- 10,11 dihydro 5 hydroxy 5H dibenzo[a,d]cycloheptene was found to be active in potentiating hexobarbital when administered intraperitoneally to mice at a dose level of -200 rug/kg.

EXAMPLE 21 2 (2 dimethylaminoethoxy) 10,11 dihydro 5- hydroxy 5 methyl 5H dibenzo[a,d]cycloheptene [1; X is CH CH Y is CH CH Z is C(CH (OH), N=B is N(CH was prepared from 2 (2 dimethylaminoethoxy) 10,11 dihydro 5H dibenzo [a,d]cyclohepten- 5-one (from 10.62 g. of the hydrochloride salt) (Example 10) and the Grignard reagent from 1.64 g. of magnesium and 4.0 ml. of methyl iodide according to the procedure described above in Example 19. The product was recrystallized from acetone to give 6.64 g. of 2-(2-dimethylaminoethoxy) 10,11 dihydro 5 hydroxy 5 methyl- SH-dibenzo[a,d]cycloheptene in the form of colorless prisms, M.P. l5l.0-152.6 C. (corn).

EXAMPLE 22 2 (2 dimethylaminoethoxy) 5 hydroxy 5 methyl 5H dibenzo[a,d]cycloheptene [1; X is CH =CH, Y is CH CH Z is C(CH )(OH), N=B is N(CH was prepared from 2 (2 dimethylaminoethoxy) 5H dibenzo[a,d]cyclohepten-5-one (from 8.09 g. of the hydrochloride salt) (Example 8) and the Grignard reagent from 1.25 g. of magnesium and 3.08 ml. of methyl iodide ac cording to the procedure described above in Example 19. The product was recrystallized from acetone to give 4.98 g. of 2 (2 dimethylaminoethoxy) 5 hydroxy 5- methyl 5H dibenzo[a,d]cycloheptene in the form of light tan prisms, M.P. 153.6 C. (corr.).

EXAMP-LE 23 5 (p chlorobenzyl) 2 (2 diethylaminoethoxy)- 5 hydroxy 5H dibenzo[a,d]cycloheptene [I; X is CH=CH, Y is CH CH Z is C(OH)(CH C H CI4), N=B is N(C H was prepared from 4.18 g. of 2-(2- diethylaminoethoxy) 5H dibenzo[a,d]cyclohepten 5- one (Example 6) and the Grignard reagent from 0.66 g. of magnesium and 4.19 g. of p-chlorobenzyl chloride. The product was chromatographed on silica gel, eluted with ether and then recrystallized from hexane to give S-(pchlorobenzyl) 2 (2 diethylaminoethoxy) 5 hydroxy 5H dibenzo[a,d]cycloheptene, M.P. 8388 C. (uncorr.).

By replacing the benzyl chloride in Example 19 by a molar equivalent amount of n-hexyl bromide or 2-phenylethyl bromide there can be obtained, respectively, -(nhexyl) 2 (2 diethylaminoethoxy) 10,11 dihydro- 5 hydroxy 5H dibenzo[a,d]cycloheptene or 5 (2- phenylethyl) 2 (2 diethylaminoethoxy) 10,11 dihydro-S-hydroxy-SH-dibenzo [a,d] cycloheptene.

By replacing the 2 (2 diethylaminoethoxy) 10,11- dihydro 5H dibenzo[a,d]cyclohepten 5 one in Example 19 by a molar equivalent amount of 2-[2-(N-benzyl N methylamino)ethoxy] 10,11 dihydro 5H- dibenzo[a,d]cyclohepten 5 one, 2 [2 (1 pyrrolidyl)ethoxy] 5H dibenzo[a,d]cyclohepten 5 one, 2- [2 (1 piperidyl)ethoxy] 5H dibenzo[a,d]cyclohepten 5 one, 3 (2 dimethylaminoethoxy) 10,11 dihydro 5H dibenzo[a,d]cyclohepten 5 one, 1 (2- diethylaminoethoxy) 5H dibenzo[a,d]cyclohepten 5- one, or 2 (2 diethylaminoethoxy) 7,8 dimethoxy- 10,11 dihydro 5H dibenzo[a,d]cyclohepten 5 one, there can be obtained, respectively, 5 benzyl 2 [2 (N- benzyl N methylamino)ethoxy] 10,11 dihydro 5- hydroxy 5H dibenzo[a,d]cycloheptene, 5 benzyl 2- [2 (1 pyrrolidyl)ethoxy] 5 hydroxy 5H dibenzo- [a,d]cycloheptene, 5 benzyl 2 [2 (1 piperidyl)- ethoxy] 5 hydroxy 5H dibenzo[a,d]cycloheptene, 5 benzyl 3 (2 dimethylaminoethoxy) 10,11 dihydro 5 hydroxy 5H dibenzo[a,d]cycloheptene, 5- benzyl 1 (2 diethylaminoethoxy) 5 hydroxy 5H- dibenzo[a,d]cycloheptene, or 5 benzyl 2 (2 diethylaminoethoxy) 7,8 dimethoxy 10,11 dihydro 5- hydroxy-SH-dibenzo [a,d] cycloheptene.

EXAMPLE 24 2 (2 dimethylaminoethoxy) 5 methylene 10,11- dihydro 5H dibenzo[a,d]cycloheptene [1; X is CH CH Y is CH CH Z is C=CH N=B is N(CH ].-2-(2- dimethylaminoethoxy) 10,11 dihydro 5 hydroxy 5- methyl 5H dibenzo[a,d]cycloheptene (4.63 g.) (Example 21) was dissolved in 300 ml. of benzene and 200 ml. of chloroform. To this solution was added ml. of a saturated solution of hydrogen chloride in ether and the mixture was allowed to stand for twenty-four hours. The solvents were distilled oif slowly, the residual suspension diluted with dry ether and the product collected and recrystallized from chloroform-benzene to give 3.80 g. of 2 (2 dimethylaminoethoxy) 5 methylene 10,11- dihydro 5H dibenzo[a,d]cycloheptene in the form of its hydrochloride salt, M.P. 188-489 C. (corr.).

By replacing the 2-(Z-dimethylaminoethoxy)-10,1l-dihydro-5-hydroxy-5-methyl-5H dibenzo[a,d]cycloheptene in Example 24 by a molar equivalent amount of S-benzyl- 2-(2-diethylaminoethoxy)-10,1l-dihydro 5 hydroxy-5H- dibenzo [a,d] cycloheptene, 5- p-chlorobenzyl) -2- Z-diethylaminoethoxy)-5-hydroxy 5H dibenzo[a,d]cycloheptene, S-(n-hexyl) 2 (Z-diethylaminoethoxy)-10,1l-dihydro-S-hydroxy 5H dibenzo[a,d]cycloheptene, or 5-(2- phenylethyl)-2-(2-diethylaminoeth0xy) 10,11 dihydro- S-hydroxy-SH-dibenzo[a,d1cycloheptene, there can be obtained, respectively, 2-(2-diethylaminoethoxy)-5-benzylidene-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene, 2 (2- diethylaminoethoxy) 5 (p-chlorobenzylidene)-5H-dibenzo [a,d] cycloheptene, 2- 2-diethylaminoeth0xy -5 nhexylidene)-l0,1l-dihydro-SH dibenzo [a,d] cycloheptenc, or 2-(2-diethylaminoethoxy) 5 (2-phenylethylidene)- 10,1l-dihydro-SH-dibenzo[a,dJcycloheptene.

EXAMPLE 25 2-(Z-dimethylaminoethoxy) 10,11 dihydro-S-rnethyl- SH-dibenzo[a,dJcycloheptene [1; X is CH CH Y is CH CH Z is CHCH N=B is N(CH ].A solution of 2.05 g. of 2-(2-dimethylaminoethoxy)-5-methylene-10, 1l-dihydro-SH-dibenzo[a,d]cycloheptene in the form of its hydrochloride salt (Example 24) in 200 ml. of ethanol was hydrogenated at room temperature in the presence of 0.25 g. of palladium-on-charcoal catalyst. After two and one-quarter hours the requisite mole-equivalent of hydrogen had been absorbed, and the mixture was filtered and concentrated to dryness. The residue was recrystallized from a chloroform-benzene mixture to give 2.01 g. of 2- (Z-dimethylaminoethoxy)-10,1l-dihydro 5 methyl-5H- dibenzo[a,d]cycloheptene in the form of its hydrochloride salt, M.P. 146.8152.0 C. (corr.).

2-(Z-dimethylaminoethoxy) 10,11 dihydro-5-methyl- SH-dibenzo[a,d]cycloheptene was found to be active at mg./kg. in reversing reserpine ptosis in mice.

By replacing the 2-(2-dimethylaminoethoxy)-5-methylcue-10,11-dihydro-5H-dibenzo[a,d]cycloheptene in Example 25 by a molar equivalent amount of 2-(2-diethylaminoethoxy)-5-benzylidene-10,1l-dihydro 5H dibenzo[a,d1 cycloheptene, 2- Z-diethylaminoethoxy -5 p-chlorobenzylidene)-5H-dibenzo [a,d] cycloheptene, 2-(2-diethylaminoethoxy)-5-(n-hexylidene) 10,11 dihydro 5H dibenzo [a,d]cycloheptene, or 2 (2 diethylaminoethoxy)-5-(2- phenylethylidene)-10,1l-dihydro-SH dibenzo[a,d]cycloheptene, there can be obtained, respectively, 2-(2-diethylaminoethoxy)-5-benzyl-l0,1l-dihydro 5H dibenzo[a,d] cycloheptene, 2-(2 diethylaminoethoxy)-5-(p -chlorobenzyl)-5H-dibenz0[a,d]cycloheptene, 2-(2-diethylaminoethheptene, or 2- 2-diethylaminoethoxy -5- Z-phenylethyl 10,1l-dihydro-SH-dibenzo[a,d]cycloheptene.

EXAMPLE 26 2-(Z-dimethylaminoethoxy)-l0,1l-dihydro S-hydroxy- SH-dibenzo[a,dJcycloheptene [1; X is CH CH Y is CH CH Z is CHOH, N=B is N(CH ].2-(2-dimethylaminoethoxy)-10,1l-dihydro 5H dibenzo[a,d]cyclo- 'hepten-S-one (from 3.98 g. of its hydrochloride salt) (Example 10), was dissolved in ml. of tetrahydrofuran, 0.91 g. of lithium aluminum hydride was added, and the mixture was stirred for six hours. The reaction mixture was filtered, the solid material slurried with hot chloroform, and the tetrahydrofuran and chloroform solutions were combined and concentrated to dryness. The residue was crystallized from 40 ml. of ether to give 2.77 g. of 2-(2-dimethylaminoethoxy)-10,11-dihydro-5-hydroxy 5H dibenzo[a,dJcyclohfiptene, M.P. 100.8103.2 C. (corr.).

EXAMPLE 27 2-(2-methylaminoethoxy)-10,1l-dihydro 5H dibenzo [a,dJcyclohepten-S-one [1; X is CH CH Y is CH CH Z is CO, N=B is NHCH ].2-[2-(N-benzyl-N-methylamino)ethoxy]-10,1l-dihydro 5H dibenzo[a,d]cyclohepten-S-one (7.39 g. of the hydrochloride salt) (Example 11) in 200 m1. of ethanol was hydrogenated at room temperature for two and one-half hours in the presence of 0.74 g. of palladium-on-charcoal catalyst. The reaction mixture was filtered, the filtrate concentrated to dryness and the residue recrystallized from isopropyl alcohol to give 4.87 g. of 2-(2-methylaminoethoxy)-10,1l-dihydro- 5H-dibenzo[a,d]cyclohepten-S-one in the form of its hydrochloride salt, M.P. 183.8186.2 C. (corr.).

2-(Z-methylaminoethoxy)-10,1l-dihydro 5H dibenzo [a,d]cyclohepten-5-one was found to be as active as imipramine in inhibiting phenylamine fi-hydroxylase.

EXAMPLE 28 (a) 2 [2-(N-carbethoxy-N-methylamino)ethoxy]-5H- dibenzo[a,d]cyclohepten-5-one.--A benzene solution of 2- [2-(N-benzyl-N-methylamino)ethoxy] 5H-dibenzo[a,d] cyclohepten-S-one (from 10.15 g. of its hydrochloride salt) (Example 12) was treated with 3.0 ml. of ethyl chloroformate. The reaction mixture was allowed to stand overnight and then refluxed for twenty-four hours. The solvents were removed in vacuo and the residue dissolved in ether and treated with an excess of hydrogen chloride in ethanol. The solid product was filtered. The filtrate was concentrated and the residue was recrystallized from nhexane to give 8.21 g. of 2-[2-(N-carbethoxy-N-methylamino)ethoxy] 5H dibenzo[a,d]cyclohepten 5 one,

13 M.P. 75-76 C. (uncorr.); infrared absorption at 3.37, 5.92, 6.15, 6.25, 6.71 and 6.75-6.85

(b) 2 (Z-methylaminoethoxy)-5H-dibenzo[a,d]cyclohepten-S-one [1; X is CH=CH, Y is CH CH Z is CO, N=B is NHCH ].--A mixture of 7.58 g. of 2-[2-(N-carbethoxy-N-methylamino)ethoxy] 5H dibenzo[a,d]cyclohepten-S-one and 7.05 g. of potassium hydroxide in 75 ml. of ethanol was refluxed for five and one-half hours. The reaction mixture was concentrated to less than half its volume, 250 m1. of water was added and the mixture extracted with ether. The ether extracts were washed with water and sodium chloride solution, dried over anhydrous magnesium sulfate and treated with an excess of hydrogen chloride in ethanol. The solid hydrochloride salt was recrystallized from isopropyl alcohol, converted to the free base and chromatographed on silica gel. The resulting material was recrystallized from n-hexane to give 2-(2-methylaminoethoxy) -5H-dibenzo[a,d] cyclohepten-S-one, M.P. 81.284.0 C. (corr.). A sample of the hydrochloride salt when recrystallized from isopropyl alcohol had the M.P. 217.5-221 C. (uncorr.).

EXAMPLE 29 (a) 2-(2 hydroxyethoxy) 10,11 dihydro-5H-dibenzo [a,d]cyclohepten-S-one.-Ethylene oxide (2 ml.) was added to a solution of 6.73 g. of 2-hydroxy-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-S-one and 2.45 g. of sodium hydroxide in 2530 ml. of water held at 5 C. The reaction mixture was stirred at -5 C. for two hours and then for two hours while allowing the solution to warm to room temperature. The mixture was stirred for two hours longer and acidified with hydrochloric acid. The solid material was separated, taken up in chloroform, and stirred and heated with excess sodium carbonate solution. The base insoluble material comprising 2-(2hydroxyethoxy 10,1 l-dihydro-SH-dibenzo [a,d] cyclohepten-S-one was isolated and used directly in the next reaction.

(b) p-Toluenesulfonate ester of 2-(2-hydroxyethoxy)- 10,11 dihydro H dibenzo[a,d]cyclohepten 5 one.- The crude 2 (2 hydroxyethoxy)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-S-one from part (a) (5.04 g.) was dissolved in 25 ml. of pyridine. The solution was cooled to 46 C. and 3.93 g. of p-toluenesulfonyl chloride in 5 m1. of pyridine was added over a period of fourteen minutes. The reaction mixture was stirred at 510 C. for two and one-half hours, allowed to stand overnight and then stirred at 2025 C. for two and one-half hours.

The reaction mixture was added to ice-water containing 80 ml. of concentrated hydrochloric acid and extracted with benzene. The benzene extracts were washed with water and sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residual 6.25 g. of oil comprising p-toluenesulfonate ester of 2-(2-hydroxyethoxy)-10,1l-dihydro-SH-dibenzo[a,dJcyclohepten-S-one was used directly in the next reaction.

(c) 2-(2-ethylaminoethoxy)-10,1l-dihydro-SH-dibenzo [a,d]cyclohpeten-5-one [1; X is CH CH Y is CH CH Z is CO, N B is NHC H ].A mixture of 5.25 g. of the p-toluenesulfonate ester of 2-(2-hydroxyethoxy)-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-S-one, 4 ml. of anhydrous ethylamine and ml. of toluene was stirred with cooling for two hours, allowed to stand overnight at room temperature and then stirred with gentle reflux for eight hours. The product was isolated, dissolved in ether and treated with an excess of hydrogen chloride in ethanol. The resulting product was recrystallized from isopropyl alcohol to give 2-(2-ethylaminoethoxy) 10,11 dihydro- SH-dibenzo[a,d]cyclohepten-5-one in the form of its hydrochloride salt, M.P. 186.0191.0 C. (corr.).

By replacing the ethylamine in the foregoing procedure by a molar equivalent amount of ammonia, cyclohexylamine, cyclopentylamine, 4-methylcyclohexylamine or 2- phenylethylamine, there can be obtained, respectively, 2- (2-aminoethoxy)-10,1l-dihydro 5H dibenzo[a,d]cyclohepten-S-one, 2-(2-cyclohexylaminoethoxy) 10,11 dihydro-5H-dibenzo[a,d]cyclohepten-S-one, 2-(2-cyclopentyl aminoethoxy) 10,11 dihydro 5H dibenzo[a,d]cyclohepten 5 one, 2-[2-(4-methylcyclohexylamino)ethoxy]- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-S-one, or 2-[2- (2 phenylethylamino)ethoxy] 10,11 dihydro 5H dibenzo [a,d cyclohepten-S-one.

We claim:

1. 2-(2-hydroxyethoxy)-10,11-dihydro 5H-dibenz0[a,d] cyclohepten-5-one.

References Cited UNITED STATES PATENTS 3,409,640 11/1968 Villiani 260590 DANIEL D. HORWITZ, Primary Examiner US. Cl. X.R.

UNITED S'ITATES PATENT OFFICE CERT] FICATE ()F CORRECTION Patent No. 3,507,920 Dated April 1, 97

.4LQhn L Schulenberg'and Sydney Archer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

"- II II Column 1, lines 18 and 32, [a,b] should read -[a,d]--, each occurrence.

Upper right-hand formula at bottom of column 2 should be labelled "III" instead of --V--.

Column 3, line 75, (HaI-L-N B)" should read --(Hal-YN=B)--.

Column 5, line 46, "d1benzo1[a ,dJcyclopenten" should read --d1benzo[a,d]cyclohepten--.

Column 6, line 57, delete entire line and insert in :lt s place: "2-acetoxy-l0, l1dihydro-5H-dibenzo[a,dlcyclohepten- Signed and sealed this 29th day of June 1971 (SEAL) Attest:

EDWARD M.FLETCHER,J-R. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

